Release of Anti-Inflammatory Palmitoleic Acid and Its Positional Isomers by Mouse Peritoneal Macrophages.

Alma M Astudillo,María A Balboa,Clara Meana,Alfonso Pérez-Encabo,Miguel A Bermúdez,Jesús Balsinde

doi:10.3390/biomedicines8110480

Abstract

Positional isomers of hexadecenoic acid are considered as fatty acids with anti-inflammatory properties. The best known of them, palmitoleic acid (cis-9-hexadecenoic acid, 16:1n-7), has been identified as a lipokine with important beneficial actions in metabolic diseases. Hypogeic acid (cis-7-hexadecenoic acid, 16:1n-9) has been regarded as a possible biomarker of foamy cell formation during atherosclerosis. Notwithstanding the importance of these isomers as possible regulators of inflammatory responses, very little is known about the regulation of their levels and distribution and mobilization among the different lipid pools within the cell. In this work, we describe that the bulk of hexadecenoic fatty acids found in mouse peritoneal macrophages is esterified in a unique phosphatidylcholine species, which contains palmitic acid at the sn-1 position, and hexadecenoic acid at the sn-2 position. This species markedly decreases when the macrophages are activated with inflammatory stimuli, in parallel with net mobilization of free hexadecenoic acid. Using pharmacological inhibitors and specific gene-silencing approaches, we demonstrate that hexadecenoic acids are selectively released by calcium-independent group VIA phospholipase A2 under activation conditions. While most of the released hexadecenoic acid accumulates in free fatty acid form, a significant part is also transferred to other phospholipids to form hexadecenoate-containing inositol phospholipids, which are known to possess growth-factor-like-properties, and are also used to form fatty acid esters of hydroxy fatty acids, compounds with known anti-diabetic and anti-inflammatory properties. Collectively, these data unveil new pathways and mechanisms for the utilization of palmitoleic acid and its isomers during inflammatory conditions, and raise the intriguing possibility that part of the anti-inflammatory activity of these fatty acids may be due to conversion to other lipid mediators.

Highlights

Accumulating evidence suggests a key role for the cis-unsaturated fatty acid palmitoleic acid in protecting against hepatic steatosis and improving overall insulin sensitivity in metabolic tissues [1,2]
We show in this paper, for the first time, that macrophages do release 16:1 fatty acids when challenged by activating stimuli, and that the process appears to be exquisitely regulated by iPLA2 -VIA
Our study constitutes the first report addressing the dynamics of 16:1 utilization by macrophages

Summary

Introduction

Accumulating evidence suggests a key role for the cis-unsaturated fatty acid palmitoleic acid (cis-9-hexadecenoic acid; 16:1n-7) in protecting against hepatic steatosis and improving overall insulin sensitivity in metabolic tissues [1,2]. Strong evidence is available to support a role for palmitoleic acid as an anti-inflammatory mediator and a positive correlate of insulin sensitivity. More research in humans is needed to validate the promising therapeutic potential of palmitoleic acid suggested by murine and in vitro studies [1,2,3,4]. Recent work has demonstrated that innate immune cells contain significant levels of a positional isomer of palmitoleic acid, cis-7-hexadecenoic acid (16:1n-9; hypogeic acid), which manifests strong anti-inflammatory properties on monocytes and macrophages [7,8,9]. Monocytes and macrophages contain significant quantities of a third 16:1 positional isomer, cis-6-hexadecenoic acid (16:1n-10; sapienic acid). 16:1n-10 exhibits anti-inflammatory activity, generally at higher concentrations than those observed for 16:1n-7 or 16:1n-9 [9]

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Results

Conclusion